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High expression of B7-H6 in human glioma tissues promotes tumor progression.

ABSTRACT: B7-H6, a new member of B7-family ligand, also known as NCR3LG1, plays an important role in NK cells mediated immune responses. Many studies have shown that it is highly expressed in various human cancers, and its expression levels are significantly associated with cancer patients' clinicopathological parameters and postoperative prognoses. But, still the exact role of B7-H6 expression in human glioma remains elusive. In the present study, we have characterized the B7-H6 expression in the human glioma tissues as well as glioma cell lines, U87 and U251. We observed that B7-H6 was highly expressed in the human glioma tissues, and its expression was significantly associated with cancer progression. By using the RNA interference technology, we successfully ablated B7-H6 expression in human glioma cell lines to further study its contribution towards various biological features of this malignancy. Our study identified that the B7-H6 knockdown in U87 and U251 glioma cells significantly suppressed cell proliferation, migration, invasion, and enhanced apoptosis along with induction of cell cycle arrest. It thus suggested that B7-H6 play an important role in the regulation of the biological behavior of these glioma cells. However, the detailed mechanism of B7-H6 mediated regulation of glioma cancer cell transformation and its prognostic value merits further investigation.

SUBMITTER: Jiang T

PROVIDER: S-EPMC5514920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Preferential Expression of B7-H6 in Glioma Stem-Like Cells Enhances Tumor Cell Proliferation via the c-Myc/RNMT Axis.

Project description:B7 homologue 6 (B7-H6), a newly identified member of the B7 costimulatory molecule family, is not only a crucial regulator of NK cell-mediated immune responses through binding to NKp30 but also has clinical implications due to its abnormal expression in human cancers. Here, we show that B7-H6 expression is abnormally upregulated in glioma tissue and that B7-H6 is coexpressed with stem cell marker Sox2. Intriguingly, B7-H6 was rarely detected on the surface of glioma cell lines but was abundantly expressed in glioma stem-like cells (GSLCs) that were derived from the glioma cell lines in vitro. Surprisingly, B7-H6 was the only one that was preferentially expressed in the GSLCs among the B7 family members. Functionally, knockdown of B7-H6 in GSLCs by siRNAs led to the inhibition of cell proliferation, with decrease in the expression of the oncogene Myc as well as inactivation of PI3K/Akt and ERK/MAPK signaling pathways. Moreover, we determined that three genes CBL (Casitas B-Lineage Lymphoma Proto-Oncogene), CCNT1 (Cyclin T1), and RNMT (RNA guanine-7 methyltransferase) were coexpressed with B7-H6 and c-myc in glioma tissue samples from the TCGA database and found, however that only RNMT expression was inhibited by the knockdown of B7-H6 expression in the GSLCs, suggesting the involvement of RNMT in the B7-H6/c-myc axis. Extending this to 293T cells, we observed that knocking out of B7-H6 with CRISPR-Cas9 system also suppressed cell proliferation. Thus, our findings suggest B7-H6 as a potential molecule for glioma stem cell targeted immunotherapy.

| S-EPMC7165331 | biostudies-literature

Expression of a novel immune checkpoint B7-H6 ligand in human small cell lung cancer.

Project description:Background:B7-H6 is a novel co-stimulatory ligand that is detected in most malignancies. However, the significance of B7-H6 in small cell lung cancer (SCLC) remains unknown. Methods:B7-H6 expression was analyzed by immunohistochemistry (IHC) in 103 collected SCLC samples, and its association with clinicopathological characteristics and prognosis was analyzed. The 2-year survival rates were also investigated. Results:B7-H6-positive staining was detected in 58 (56.31%) SCLC cases, and found to be localized mainly in the intracellular space of SCLC. Weak staining in lung tissues was observed in 4 (8%) cases. B7-H6 positive staining was significantly related to tumor-node-metastasis stage (P=0.028), age (P=0.001), and distant metastasis (P=0.033), whereas there was no association with smoking status, sex, mass size, limited-stage SCLC/extensive-stage SCLC, Karnofsky performance status, or nodal metastasis status. The 2-year survival rates showed that there were more patients whose survival was shorter than 2 years in the B7-H6-positive group compared with the B7-H6-negative group (P=0.042). Conclusions:Our findings suggest that B7-H6 is involved in early-stage SCLC and could serve as an early marker to predict human SCLC progression and distant metastasis. B7-H6 may be a valuable therapeutic target with potential clinical applications in the future.

| S-EPMC7290544 | biostudies-literature

Upregulation of B7-H4 promotes tumor progression of intrahepatic cholangiocarcinoma.

Project description:Recent reports show that B7-H4 is highly expressed in a variety of tumor cells, functions as a negative regulator of T cells and then promotes tumor progression. However, its expression and role in intrahepatic cholangiocarcinoma (ICC) remain unclear. In present study, B7-H4 expression in ICC and peritumoral tissues was determined at the level of mRNA and protein, and its bioactivity in ICC cells was studied after modification of B7-H4 expression. Then, the mechanism related to tumor progression induced by B7-H4 expression in ICC cells was explored. Finally, clinical significance of B7-H4 expression in ICC patients was further analyzed. The results showed that B7-H4 expression in ICC was much higher than that in peritumoral tissues at the level of both mRNA and protein. The high level of B7-H4 in ICC cells induced epithelial-to-mesenchymal transitions and promoted invasion and metastasis of tumor cells through activation of ERK1/2 signaling. The elevated B7-H4 expression was associated with the downregulated Bax, upregulated Bcl-2 expression, and activation of caspase-3. Clinically, high B7-H4 expression in tumor samples was significantly related to malignant phenotype, such as lymph node metastasis, high tumor stage, and poor differentiation. ICC patients with high expression of B7-H4 had shorter overall survival (OS) and disease-free survival. Moreover, the B7-H4 expression was an independent prognostic factor for predicting OS and tumor recurrence of ICC patients after operation. In conclusion, high expression of B7-H4 promotes tumor progression of ICC and may be a novel therapeutic target for ICC patients.

| S-EPMC5870586 | biostudies-literature

Structure of the human activating natural cytotoxicity receptor NKp30 bound to its tumor cell ligand B7-H6.

Project description:Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumor cells. In humans, the activating natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46 play a major role in NK cell-mediated tumor cell lysis. NKp30 recognizes B7-H6, a member of the B7 family which is expressed on tumor, but not healthy, cells. To understand the basis for tumor surveillance by NCRs, we determined the structure of NKp30, a member of the CD28 family which includes CTLA-4 and PD-1, in complex with B7-H6. The overall organization of the NKp30-B7-H6-activating complex differs considerably from those of the CTLA-4-B7 and PD-1-PD-L T cell inhibitory complexes. Whereas CTLA-4 and PD-1 use only the front ?-sheet of their Ig-like domain to bind ligands, NKp30 uses both front and back ?-sheets, resulting in engagement of B7-H6 via the side, as well as face, of the ?-sandwich. Moreover, B7-H6 contacts NKp30 through the complementarity-determining region (CDR)-like loops of its V-like domain in an antibody-like interaction that is not observed for B7 or PD-L. This first structure of an NCR bound to ligand provides a template for designing molecules to stimulate NKp30-mediated cytolytic activity for tumor immunotherapy.

| S-EPMC3135353 | biostudies-other

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells.

Project description:Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses. Using luciferase reporter assays and chromatin immunoprecipitation we mapped a functional binding site for Myc, a proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter. Pharmacological inhibition or siRNA/shRNA-mediated knock-down of c-Myc or N-Myc significantly decreased B7-H6 expression on a variety of tumor cells including melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines from different origin and primary tumor tissues of hepatocellular carcinoma (HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc in tumor cells impaired NKp30-mediated degranulation of NK cells was observed. Thus, our data imply that Myc driven tumors could be targets for cancer immunotherapy exploiting the NKp30/B7-H6 axis.

| S-EPMC5007025 | biostudies-literature

Immune checkpoint molecules B7-H6 and PD-L1 co-pattern the tumor inflammatory microenvironment in human breast cancer.

Project description:B7-H6 and PD-L1 belong to the B7 family co-stimulatory molecules fine-tuning the immune response. The present work investigates the clinical effect of B7-H6 protein expression with PD-L1 status and the infiltration of natural killer cells as potential biomarkers in breast tumor inflammatory microenvironment. The expression levels of B7-H6 protein by cancer cells and immune infiltrating cells in human breast cancer tissues and evaluate their associations with PD-L1 expression, NK cell status, clinical pathological features and prognosis were explored. The immunohistochemistry labeling method was used to assess B7-H6 and PD-L1 proteins expression by cancer and immune cells. The associations between immune checkpoint, major clinical pathological variables and survival rates were analyzed. B7-H6 protein was depicted in both breast and immune cells. Results showed that Tumor B7-H6 expression is highly associated with Her-2 over expression. B7-H6 + immune cells are highly related to the Scarff-Bloom-Richardson grade and associated with PD-L1 expression and NK cells status. Survival analysis revealed a better prognosis in patients with low expression of B7-H6 by cancer cells. Conversely, B7-H6 + immune cells were significantly associated with longer survival. Findings strongly suggest an interaction between B7 molecules that contributes to a particular design of the inflammatory microenvironment. This may influence the efficiency of therapies based on antibodies blocking the PD-L1/PD1 pathway and can explain the detection of clinical benefits only in a fraction of patients treated with immune checkpoint inhibitors.

| S-EPMC8024320 | biostudies-literature

Expression of B7-H6 in chronic myeloid leukemia and its clinical significance.

Project description:OBJECTIVE:To examine the expression level of B7-H6 in chronic myeloid leukemia (CML) patients and to explore its clinical significance. METHODS:Two hundred twenty-eight CML patients were included and peripheral blood (PB) and bone marrow (BM) mononuclear cells were collected for B7-H6 mRNA expression analyses by quantitative real time polymerase chain reaction (PCR). RESULTS:The expression of B7-H6 mRNA was successfully detected in all PB and BM samples. According to the clinical characteristics of CML patients, no difference was found in the B7-H6 level of PBMCs. However, a significantly decreased B7-H6 level was noted in BM samples from CML with BCR-ABL1/ABL > 0.1% (10 copies of BCR-ABL1/10000 copies of ABL) compared to ≤ 0.1% (P < 0.0001), and a negative correlation was found between the expression level of B7-H6 in BM and the number of BCR-ABL1/ABL transcripts (r = -0.26, P = 0.0057). A significant difference in PFS was observed between patients with high expression level of B7-H6 and low expression level in BM (χ2 = 12.53, P = 0.0004). CONCLUSION:The expression of the B7-H6 gene in CML is correlated with BCR-ABL1 copy number and responsiveness to treatment, and monitoring of B7-H6 expression may be used to predict CML prognosis, progression, and treatment efficacy evaluation.

| S-EPMC6945099 | biostudies-literature

Clinical significance of novel costimulatory molecule B7-H6 in human breast cancer.

Project description:B7 homolog 6 (B7-H6), a member of the B7 family, is as a cell-surface ligand for natural cytotoxicity triggering receptor 3, which is expressed on natural killer cells. It has previously been reported that B7-H6 is undetectable in normal human tissues but is expressed on tumor cells. However, there are few studies focusing on the clinical significance of B7-H6 expression in human carcinoma, with the exception of three studies on ovarian, lung and gastric cancer. The present study investigated the expression of B7-H6 protein in pathologic tissue samples from 305 patients with breast cancer using immunohistochemistry. A high B7-H6 expression level was identified in tissues from 32.13% of patients with breast cancer. These patients were revealed to also exhibit a high expression level of human epidermal growth factor receptor 2, a shorter survival time and a higher rate of lymph node metastasis. Furthermore, the expression level of B7-H6 was not associated with patient age, breast cancer subtype, tumor size, tumor location or estrogen receptor expression. The results of the present study revealed that higher B7-H6 expression level in breast cancer tissues was positively associated with tumor progression. This indicates that B7-H6 is associated with the progression and immunoevasion of human breast cancer; however, the molecular mechanisms underlying this potential effect require further investigation.

| S-EPMC5530087 | biostudies-other

Expression data from human glioma tissues

Project description:Gliomas are aggressive lethal solid brain tumors arising from support cells in the central nervous system. Despite intense efforts to optimize the treatment of gliomas, the outcomes of high grade glioma patients are still frustrating. The causes and progress of gliomas have been investigated extensively; however, the genetic factors involved in the development of this disease remain poorly understood. We used microarrays to detail the global program of gene expression in different grade glioma tissues and try to find out some genes associated with the tumorigenesis of gliomas. Grade I to grade IV glioma tissues were selected in surgical operations for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain gene expression profiles. To that end, we hand-selected several genes that were differentially expressed in different grade glioma tissues and then performed a further study to identify the role of these genes in the process of the development of gliomas.

| S-ECPF-GEOD-45921 | biostudies-other

Tumor Marker B7-H6 Bound to the Coiled Coil Peptide-Polymer Conjugate Enables Targeted Therapy by Activating Human Natural Killer Cells.

Project description:Targeted cancer immunotherapy is a promising tool for restoring immune surveillance and eradicating cancer cells. Hydrophilic polymers modified with coiled coil peptide tags can be used as universal carriers designed for cell-specific delivery of such biologically active proteins. Here, we describe the preparation of pHPMA-based copolymer conjugated with immunologically active protein B7-H6 via complementary coiled coil VAALEKE (peptide E) and VAALKEK (peptide K) sequences. Receptor B7-H6 was described as a binding partner of NKp30, and its expression has been proven for various tumor cell lines. The binding of B7-H6 to NKp30 activates NK cells and results in Fas ligand or granzyme-mediated apoptosis of target tumor cells. In this work, we optimized the expression of coiled coil tagged B7-H6, its ability to bind activating receptor NKp30 has been confirmed by isothermal titration calorimetry, and the binding stoichiometry of prepared chimeric biopolymer has been characterized by analytical ultracentrifugation. Furthermore, this coiled coil B7-H6-loaded polymer conjugate activates NK cells in vitro and, in combination with coiled coil scFv, enables their targeting towards a model tumor cell line. Prepared chimeric biopolymer represents a promising precursor for targeted cancer immunotherapy by activating the cytotoxic activity of natural killer cells.

| S-EPMC8615638 | biostudies-literature

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